Genetic Variant KCP:p.Arg1560Cys (chr7-128877252-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001366122.1(KCP):c.4678C>T(p.Arg1560Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,489,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1560H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

KCP
NM_001366122.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.749

Publications

0 publications found

Variant links:

Genes affected

KCP (HGNC:17585): (kielin cysteine rich BMP regulator) Predicted to act upstream of or within hematopoietic progenitor cell differentiation and positive regulation of BMP signaling pathway. Predicted to be located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

KCP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1419594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCP	NM_001366122.1 link	c.4678C>T	p.Arg1560Cys	missense_variant	Exon 40 of 40	ENST00000610776.5	NP_001353051.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCP	ENST00000610776.5 link	c.4678C>T	p.Arg1560Cys	missense_variant	Exon 40 of 40	5	NM_001366122.1	ENSP00000479679.1		A0A087WVT8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000290

AC:

AN:

103530

AF XY:

0.0000183

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000241

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.0000464

AC:

AN:

1336860

Hom.:

Cov.:

AF XY:

0.0000504

AC XY:

AN XY:

654126

show subpopulations

African (AFR)

AF:

0.0000347

AC:

AN:

28860

American (AMR)

AF:

0.00

AC:

AN:

22382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21562

East Asian (EAS)

AF:

0.0000284

AC:

AN:

35150

South Asian (SAS)

AF:

0.0000286

AC:

AN:

69988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46794

Middle Eastern (MID)

AF:

0.000406

AC:

AN:

4926

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1052060

Other (OTH)

AF:

0.0000544

AC:

AN:

55138

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000784

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4303C>T (p.R1435C) alteration is located in exon 36 (coding exon 36) of the KCP gene. This alteration results from a C to T substitution at nucleotide position 4303, causing the arginine (R) at amino acid position 1435 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.16

T;.;T

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.83

T;T;T

MetaRNN

Benign

0.14

T;T;T

PhyloP100

0.75

PrimateAI

Benign

0.44

Sift4G

Uncertain

0.0070

D;D;D

Vest4

0.23

MVP

0.38

GERP RS

4.5

Varity_R

0.11

gMVP

0.45

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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7-128877252-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over